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    1528723 1-Nitro-9-N-alkylaminoalkylaminoacridines POLITECHNIKA GDANSKA 22 Feb 1977 [25 Feb 1976] 07288/77 Heading C2C Novel compounds of the Formula I wherein R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, benzyl or cyclohexyl and n is 2 or 3 and acid addition salts thereof, may be prepared by reacting 1-nitro-9-phenoxy-acridine with a corresponding N-substituted amino-C 2 or C 3 alkylamine. 1-Nitro-phenoxyacridine is prepared by reacting 1-nitro-9-chloroacridine or (1-nitroacridyl-9)-pyridinium chloride with phenol. The product can be reacted in situ to form a Compound I. Pharmaceutical compositions of the Compound I with the usual excipients show antineoplastic and spasmolytic activity when administered parenterally.
    公开号:SU719498A3
    申请号:SU772452268
    申请日:1977-02-18
    公开日:1980-02-29
    发明作者:Высоцка-Скщэля Барбара；Ледуховски Андзей；Радзиковски Чэслав；Хоровска Барбара；Гелдановски Ежы；Савиньска Люцына；Мэдонь Мечыслав；Квасневска-Рокициньска Цэцыля
    申请人:Политехника Гданьска (Фирма)；
    IPC主号:
    专利说明:

    As salts of compounds of general formula I, it is necessary to mention salts of inorganic acids, for example, chlorohydrates, hydrobromides, sulfates, or organic acids, for example, lactates, citrates, succinates. Example 1. 15 g of phenol are added to 3.4 g of (1-nitroacridyl-9) -ridium diphenyl chloride and heated for 15 minutes at 50 ° C. After cooling, 2.1 g of 3-isopropylpylaminopropylamine dihydrochloride are added and the mixture is heated again for 45 minutes at a temperature of 80 ° C. The mixture obtained after the reaction is cooled, 20 ml of benzene are added, and then slowly poured into a concentrated 20% solution of hydroxide. After alkalinization, the reaction mixture is extracted with benzene. The combined benzene extracts are dried over anhydrous magnesium sulphate and, after filtration of the drying agent, an ethereal solution of hydrogen chloride is added. The precipitated orange oil is dissolved in anhydrous ethanol, heated with activated carbon, filtered, dry ether is added and left to crystallize. Orange crystals of 1-nitro-9-isopropylaminopropylaminoacridine dichlorohydrate are obtained with a melting point of about 230 ° C (with decomposition). The yield is 78%. Similarly, get citrate - with t. Nl. about 300 ° C, tartrate-, with so nl. 150 ° C. Chromatographic analysis: on neutral alumina (type E) in the system benzene - ethyl acetate - ammcac (15: 59: 1), 6Q. Calculated,%: C 55.79; H 5.90; N 13.70. Ci9H24N4O2Cl2. Found,%: C 55.96; H 5.66; N 13.61. Example 2. 2.51 g of 1-nitro-9-chloroacridine is dissolved in 10 g of phenol, heated for 15 minutes at 60 ° C, then cooled, and then 1 g of N-ethylaminopronylamine is added and heated again for 30 minutes at 90 ° C . The reaction mixture is cooled, added with 20 ml of ether, and this mixture is poured into an excess of ether (about 500 ml). The solution is acidified with ether solution of hydrogen chloride and the precipitated precipitate is filtered off and recrystallized twice from absolute alcohol. 2.8 g of 1-nitro9-ethylaminopropylaminoacridine dihydrochloride are obtained. C. m.p. about 225 ° C (with decomposition). Chromatographic analysis on neutral alumina (type E) in the system: cyclohexane-acetone-ammonia (37: 37: 1) / 0.54. Calculated,%: C 52.68; H 5.67; N 13.87. C6H2202N4C12-V2H20. Found,%: C 52.65; H 5.45; N 13.73. Example 3. 2g (1-nitroacridyl-9) -pyridinium chloride is heated with 10 g of phenol for 10 minutes at a temperature of 80 ° C. After 719498 l Cooling, 1.5 g of benzylaminopropylamine dihydrochloride are added and the mixture is heated again at 100 ° C for 1 h. After cooling, the mixture is poured into a large amount of an aqueous solution of sodium hydroxide. The oily residue is extracted with ethyl acetate. Addition of 1-nitro-9-benzylaminopropylaminoacridine dichlorohydrate is precipitated with the addition of an ethereal solution of hydrogen chloride, which is crystallized from a mixture of methanol and ether. Obtain 1.25 g (50%) of 1-nitro-9 dichlorohydrate - benzylaminopropylaminoacridine with m. Pl. 198 ° C. Chromatographic analysis of neutral alumina (tin E) in the system: cyclohexane - ethyl acetate - ammonia (37:: 37: 1), 37. Calculated,%: C 57.86; H 5.49; N 11.74. C23H24N4O2C12. Found,%: C 57.72, H 5.26; N 11.60. Example 4. 2 g of (1-nitroacridyl-9) -pyridinium chloride and 10 g of feiol are heated for 10 minutes at a temperature of 80 ° C, cooled, and 1.3 g of isopentylamine opronylamine dihydrochloride are added and heated for 1.5 hours at 100 ° C . The precipitate was isolated in the same manner as in Example 3. 1.25 g (50%) of 1-nitro-9 dichlorohydrate — isonentilaminopropylaminoacridine with m.p. 180 ° C (with decomposition). Chromatographic analysis of i-trap aluminum oxide (type E) in the system: cyclohexane-ethyl acetate-ammonia (37:: 37: 1)., 50. Calculated,%: C 55.15; H 6.61; N 12.25. C2iH28N402Cl2-H20. Found,%: C 55.53; H 6.67; N 12.23. Example 5. 3.4 g (1-nitroacridyl-9) -pyridinium chloride and 15 g of phenol are heated for 10 minutes at a temperature of 80 ° C. After cooling, 1.16 g of propylaminonropylamine is added and the mixture is heated for 1.5 hours at 100 ° C. Process analogously to example 3 and get 1.8 g of 1-nitro-9-propylaminopropylamio-acridine dichlorohydrate with m.p. 234 ° C (with decomposition). Chromatographic analysis of neutral alumina (type E) in the system of benol-methanol (10: 1), 4. Calculated,%: C 55.47; H 5.88; N 13.62. C19H2d: L4O2C12. Found,%: C 55.48; H 5.87; N 1,3,51. Example 6. 3.4 g (0.01 mol) of (i-nitro-nitrile-9) -pyridinium chloride and 15 g of phenoheated are heated for 15 minutes at a temperature of 80 ° C, cooled, 1.6 g of 3-methylaminopropylamine dihydrochloride are added and heated, 5 hours at a temperature of 80 ° C. - Analogously as in Example 1, 1-nitro-9- (3-methylamine-propylamino) -acridine dichlorohydrate is obtained in dark yellow veta with m.p. 255 ° С (with decomposition). Chromatographic analysis on neutral alumina (type E) in the heptane-acetone-ammonia system (35: 35: 1) -R / 0., 27. Calculated,%: G 52.68; H 5.29; N 14.38.
    Ci7H2oN4O2Cl2.
    Found,%: C 52.35; H 5.35; N 14.63.
    Example 7. 3.4 g (1-nitroacridyl-9) pyridinium chloride is dissolved in 10 g of phenol and heated for 15 minutes at a temperature of 80 ° C. After cooling, 2.1 g of 3-butylaminopropylamine hydrochloride is added, heated again for 1 hour at 80 ° C, cooled, ether is added and the mixture is poured into a cooled aqueous solution of sodium hydroxide. Extracted with ether, dried and added ethereal hydrogen chloride solution.
    The precipitated hygroscopic precipitate is crystallized several times from a mixture of absolute ethanol and ether.
    1-nitro-9-butylaminopropylaminoacridine dihydrochloride is obtained with a yield of 62%, with an mp. 215 ° C (with decomposition).
    Thin-layer neutral alumina chromatography (type E) in a benzene-ethyl acetate-ammonia system (15:59: 1). 0.86.
    Calculated,%: C 55.60; H 5.94; N 12.97.
    С2оН2бМ4О2С12.
    Found,%: C 55.43; H 5.98; N 12.70.
    Example 8. 1.7 g (1-nitroacridyl-9) -pyridinium chloride and 10 g of phenol are heated for 10 minutes at 80 ° C. After cooling, 1.15 g of cyclohexylaminopropylamine hydrochloride is added and the mixture is again heated at 100 ° C for 2 hours. The reaction mixture is then dissolved in ether and slowly poured into a cooled solution of potassium hydroxide and extracted several times with ether. After pre-drying, the ether extract is distilled to half the volume.
    The resulting residue is cooled and filtered, and the resulting 1-nitro-9-cyclohexylaminopropylaminoacridine. The base is recrystallized from ether-benzene. Melting point 150 ° C (with decomposition). The resulting product can be converted to salt.
    The product is isolated in the form of hydrochloride.
    Calculated,%: C 56.29; H 6.44; N 11.94.
    C22H23N4O2C12-H2O.
    Find%: C 56.15; H 6.33; N 11.70.
    Chromatographic analysis on neutral alumina (type E) in the benzene-methanol system (10: 1)., 3.
    Example 9. 3.4 g (0.01 mol) of (1-nitroacridyl-9) -pyridinium chloride are heated with 15 g of phenol for 15 minutes at 60 ° C, cooled, 1.5 g of methylaminoethylamine dichlorohydrate are added and heated again at a temperature of 80 ° C for 0.5 h. Cool, alkalinize with 10% sodium hydroxide solution. The precipitated orange precipitate of 1-nitro-9- (2-methylaminoethylamino) -acridine monochlorohydrate is dried, suspended in a small amount of ether (due to its complete insolubility in either ether or benzene) and
    acidified with ethereal chloride solution
    hydrogen. After crystallization from dry
    methanol get dichlorohydrate 1-nitro9-methylaminoethylaminoacridine with the release
    65% and so on. Pl. 255 ° С (with decomposition).
    Neutral alumina chromatography (type E) in the system: benzene-acetone-ammonia (3: 1: 2), 46. Calculated,%: C 52.65; H 4.97; 15.35.
    Ci6Hi8N4O2Cl2.
    Found,%: C 52.49; H 5.01; N 15.21.
    Example 10. 1.7 g (1-nitroacridyl-9) pyridinium chloride, 10 g of phenol is heated for 15 minutes at a temperature of 80 ° C. After cooling, 1.1 g of cyclohexylaminoethylamine dichlorohydrate is added and heated again for 2 hours at a temperature of l2 (fC. The condensation product is isolated as in Example 9.
    Obtain 2.4 g (55%) of 1-nitro-9 - cyclohexylaminoethylaminoacridine dichlorohydrate with m.p. 280 ° C (with decomposition).
    Chromatographic analysis on neutral alumina (type E) in the system cyclohexane - ethyl acetate - ammonia (37:: 37: 1), 37.
    Calculated,%: C 57.58; H 6.21; N 12.79.
    C2iH27N4O2Cl2.
    Found,%: C 57.71; H 6.23; N 12.82.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 1-nitro-9-alkylaminoalkylaminoacridines of the general formula
    N02 MN (
    where n is 2 or 3;
    R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, benzyl or cyclohexyl,
    or their salts, characterized in that
    (1-nitroacridyl-9) - pyridinium chloride or 1-nitro-9-chloroacridine or their salts are mixed with phenol and heated to a temperature of 50-80 ° C, the mixture is cooled to room temperature and subjected to interaction with alkylaminoalkylamine formula
    NH, (CH,) „NHR,
    where rt and R have the indicated meanings,
    or its salt at a temperature of 50-120 ° C,
    cooled, poured into non-polar organic solvent which is not miscible with water, the precipitated precipitate of 1-nitro-9-alkylaminoalkylamino-amino-amidine monochlorohydrate is filtered off and treated with ethereal hydrogen chloride solution and about 78
    Rytsuyu1tsii dichlbrgidrat crystallized with a solvent, dried and crystallized from an organic solvent, or mono-ly or hesitate to salt,
    1-nitro-9-alkylaminoalkyl hydrochloride-Sources of information
    Noacridine is alkalinized with a guide-to-take solution into account when examining
    alkaline oxide alkali metal, extragyr-5 1. USSR Patent No. 366194, cl. From 07D
    Organic-219/12, non-water-biased, are published. 1973.
    719498
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